Iodine-Promoted Tunable Synthesis of 2-Naphthyl Thioethers and 1-Naphthyl Thioethers

Article abstract of DOI:10.1002/adsc.201801562

An iodine-promoted regioselective sulfenylation/deoxygenation/aromatization reaction of 1-tetralones with disulfides has been developed. This process could be modified to synthesize 2-naphthyl thioethers and 1-naphthyl thioethers in moderate to excellent

Full text of DOI:10.1002/adsc.201801562

Title: Iodine-Promoted Tunable Synthesis of 2-Naphthyl Thioethers and
1-Naphthyl Thioethers
Authors: Yishu Bao, Xiuqin Yang, Zonghao Dai, Suyu Ji, Qing-Fa
Zhou, and Fulai Yang
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201801562
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10.1002/adsc.201801562
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Iodine-Promoted Tunable Synthesis of 2-Naphthyl Thioethers
and 1-Naphthyl Thioethers
Yishu Bao,a Xiuqin Yang,a Zonghao Dai,a Suyu Ji,a Qingfa Zhou a* and Fulai Yanga*
a
State Key Laboratory of Natural Medicines, Department of Organic Chemistry, China Pharmaceutical University,
Nanjing, 210009, P. R. China.
Fax: (+86)-025-8628-5179; Phone: (+86)-025-8618-5160; Email: zhouqingfa@cpu.edu.cn; fly1986@ustc.edu.cn
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
unactivated
cyclohexanones
to
give
2-
Abstract.
An
iodine-promoted
regioselective
sulfenylation/deoxygenation/aromatization reaction of 1- sulfanylphenols with retention of an oxygen atom.
tetralones with disulfides has been developed. This process
could be modified to synthesize 2-naphthyl thioethers and
1-naphthyl thioethers in moderate to excellent yields,
respectively. Furthermore, when the reaction was extended
to 2-tetralones, 2-naphthyl thioethers were obtained as the
sole products. The current study bridges the deoxygenation
and sulfenylation/aromatization of ketones, thus providing
a new tool in organic synthesis.
Nevertheless, to the best of our knowledge, tandem
deoxygenation and sulfenylation/aromatization of
ketones with sulfenylating agents have never been
documented.
Very recently, we have developed a new iodine-
promoted protocol for the synthesis of β-iodoalkenyl
sulfides
via
tandem
deoxygenated
iodization/olefination/sulfenylation of ketones with
sulfonyl hydrazides.[11] Intriguingly, we found that
ketones could react with disulfides to give a trace
amount of vinyl sulfides. Encouraged by this result,
we investigated whether this reaction could be
optimized into a synthetically useful transformation.
To our surprise, this process afforded not only 2-
naphthyl thioethers but also 1-naphthyl thioethers
(Scheme 1).
Keywords: Tetralones; Disulfides; Iodine; Deoxygenation;
Synthetic methods
The selective formation of C(sp2)-S bonds is a
fundamental transformation in organic synthesis.[1]
Recent years have witnessed a growing interest in
transition-metal-catalyzed cross-coupling reactions of
carbon-halides[2] or carbon-boronic acids/esters[3]
with sulfenylating agents to form C(sp2)-S bonds.
Despite considerable advances, in view of sustainable
and green chemistry, these reactions have several
limitations. Therefore, developing alternative
methodologies that could be advantageous in terms of
Scheme 1. Iodine-Promoted Tunable Synthesis of 2-
Naphthyl Thioethers and 1-Naphthyl Thioethers.
catalyst,
availability
of
starting
materials,
convenience of manipulation, substrate scope, and
environmental friendliness is one of the research
hotspots in organic synthesis.
The reaction of 1-tetralones (1a) with disulfides
(2a) was selected as a model reaction. Initially,
various solvents were screened, and satisfactory
regioselectivity and yield of 2-naphthyl thioether 3a
(83%, 3a:7a 14:1) were achieved when using CHCl3
as the solvent, while n-hexane afforded a moderate
yield with poor regioselectivity. Running the reaction
in CHCl3 (1.5 mL) yielded a better result (88%, 3a:7a
20:1). Heating the mixture at 110 °C led to a higher
yield but poorer regioselectivity (94%, 3a:7a 12:1). It
is worth noting that the ratio of starting materials is
crucial for the regioselectivity. Raising the ratio of 1a
and 2a gave poorer regioselectivity. Thus, the optimal
reaction conditions for 2-naphthyl thioether 3a
synthesis were 2.0 equiv. of 1a, 1.0 equiv. of 2a and
The carbonyl group, which is a reactive center for
a wide range of functional group transformations, is
among the most fundamental functionalities in
organic
chemistry.[4]
Among
them,
both
deoxygenation[5] and α-sulfenylation[6] have long been
important pursuits in the synthetic community. Many
impressive accomplishments have been achieved in
these fields; for example, well-known milestones in
the deoxygenation of ketones include the Wolff-
Kishner-Huang reaction,[7] the Bamford-Stevens-
Shapiro Olefination[8] and the Clemmensen
Reduction.[9] Sulfenylation of ketones has also made
great progress. Recently, Wei[10] reported excellent
studies on the sulfenylation/aromatization of
1
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10.1002/adsc.201801562
Advanced Synthesis & Catalysis
1.0 equiv. of I2 in CHCl3 at 90 °C. The optimization
of the above reaction conditions suggests that using
n-hexane as a solvent, raising the temperature and
increasing the loading of 1a favored the formation of
1-naphthyl thioether 7a. In addition, replacing iodine
with NIS, TBAI and NBS led to much lower yield.
Decreasing the amount of I2 with adding TBHP or
H2O2 failed to give higher yields. Interestingly, a
change in regioselectivity was observed when the
temperature was raised to 120 °C, and the ratio of 1a
and 2a was adjusted to 4:1. Further examination
showed that the optimal reaction conditions for the
synthesis of 1-naphthyl thioether 7a were 4.0 equiv.
of 1a, 1.0 equiv. of 2a and 1.5 equiv. of iodine in n-
hexane at 120 °C (Table S1 in the Supporting
Information).
With the optimized reaction conditions identified,
we then investigated the substrate scope of this novel
reaction. The scope of the disulfides was first
examined, and the results are summarized in Table 1.
A range of substituted aryl disulfides 2 could react
with 1-tetralones 1 to give structurally diverse 2-
naphthyl thioethers 3 in moderate to excellent yields.
Halogen substitution in the aromatic rings was
tolerated in this protocol (3c-3f, 3j, 3k), enabling
further derivatization through cross-coupling
reactions. In addition, acceptable yields were
obtained when strong electron-rich and strong
electron-deficient substituents on the benzene ring
were applied in this transformation (3g, 3i). However,
no product was detected from the reaction between
dimesityldisulfane and 1-tetralone (3l), most likely
owing to the steric repulsion in the sulfenylation step.
As we hoped, this optimized protocol can also be
applied to aliphatic disulfides (3o-3s).
Subsequently, the reaction was successfully
[12]
extended to 1-tetralones (Table 2).
The desired
reaction worked well when 4-methyl 1-tetralone was
applied under standard conditions (4a), while
replacing the methyl group with aryl groups resulted
in moderate yields (4b, 4c). 1-Tetralones with both
electron-rich and electron-deficient functional groups
on the phenyl ring gave the desired products in good
yields (4d, 4e, 4h-4k, 4l). Notably, when the C-6
position of 1-tetralone was occupied by an OH group,
a strong electron-donating group, desired products
underwent
further
sulfenylation
to
give
disulfenylation compounds (4f, 4g) as the only
products with high regioselectivity.[13]
Table 2. The Scope of 1-Tetralones 1 for Synthesis of 2-
Naphthyl Thioethers 4.[a]
[a] Reaction conditions: 1 (0.2 mmol), 2 (0.1 mmol), I2 (0.1
mmol), CHCl3 (1.5 mL), under air in a sealed tube at
90 °C (oil bath) for 12 h.
[b] 2 (0.2 mmol), at 130 °C, for 24 h.
[c] 1 (0.4 mmol), at 110 °C.
Furthermore, when 2-tetralones (5) were
investigated under standard conditions, 2-naphthyl
thioethers were observed as the sole products, which
is different from the iodine-promoted reaction of 1-
tetralones with disulfides. This reaction showed a
wide scope and functional-group tolerance with good
yields, and selected examples are presented in Table
3.
Table 1. The Scope of the Disulfides 2 for Synthesis of 2-
Naphthyl Thioethers 3.[a]
Table 3. The Scope of 1-Tetralones 5 with Disulfides 2 for
Synthesis of 2-Naphthyl Thioethers 6. [a]
[a] Reaction conditions: 1 (0.2 mmol), 2 (0.1 mmol), I2 (0.1
mmol), CHCl3 (1.5 mL), under air in a sealed tube at
90 °C (oil bath) for 12 h.
[a] Reaction conditions: 1 (0.2 mmol), 2 (0.1 mmol), I2 (0.1
mmol), CHCl3 (1.5 mL), under air in a sealed tube at
90 °C (oil bath) for 12 h.
[b] 2 (0.2 mmol), at 130 °C, for 24 h.
[b] 1 (0.4 mmol) at 120 °C.
[c] 1 (0.4 mmol), at 110 °C.
2
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10.1002/adsc.201801562
Advanced Synthesis & Catalysis
Lastly, the scope of 1-tetralones and disulfides was
reaction mixture under standard conditions had a
minor effect on the yield (eq (2)), suggesting this
reaction might not involve a radical intermediate.
Furthermore, to clarify the hydrogen source that
previously placed the carbonyl group, several
deuterium-labeling experiments were conducted. No
deuterium incorporation at the C-1 position was
observed for the reaction of deuterated 1-tetralones
(10 and 11) with disulfides (eqs (3) and (4)); however,
when polydeuterated 1-tetralone (12) was subjected
to standard conditions, 2-naphthyl thioether with 25%
deuterium incorporation at the C-1 position was
observed (eq (5)). Moreover, a crossover experiment
was performed using a 1:1 mixture of polydeuterated
1-tetralone 12 and undeuterated 6-methoxy-1-
tetralone, giving no deuterium incorporation product
3i (eq (6)), which implies that the hydrogen transfer
might undergo an intramolecular process. These
examined for the synthesis of 1-naphthyl thioethers 7.
As shown in Table 4, a range of aryl- and
alkyldisulfides
smoothly
underwent
the
sulfenylation/deoxygenation/aromatization reaction
with 1-tetralone in n-hexane to give structurally
diverse thioethers in moderate to good yields.
Table 4. The Scope of the 1-Tetralones 1 with Disulfides 2
for Synthesis of 1-Naphthyl Thioethers 7.[a]
reaction
outcomes
demonstrate
that
a
hydrogen/deuterium shift occurred from C-3 to C-1,
consistent with our previous reports on byproduct-
catalyzed
tandem
sulfenylation/deiodination/aromatization of cyclic
alkenyl iodides with sulfonyl hydrazides.[14] However,
no cyclic alkenyl iodide was detected in the reaction
mixture of 1a and 2a. Therefore, we speculate that
this new protocol might undergo an intermediate
similar to the cyclic alkenyl iodide.
[a] Reaction conditions: 1 (0.4 mmol), 2 (0.1 mmol), I2 (0.3
mmol), n-hexane (1.5 mL), under air in a sealed tube at
120 °C (oil bath) for 12 h.
[b] 1 (0.4 mmol), in CHCl3 (1.5 mL), at 110 °C.
[c] 2 (0.25 mmol), at 130 °C, for 24 h.
To further show the synthetic potential of our new
reaction, a gram-scale reaction was performed using
5 mmol (731.0 mg) of 1-tetralone 1a, giving 2-
naphthyl thioether 3a in 86% yield (1.08 g) (Scheme
2). Treatment of 4g with CuTc in AcNMe2 afforded
the compound 8 in 78% yield.
Scheme 3. Control Experiments.
Scheme 2. Gram-Scale Synthesis and Synthetic
Transformations.
According to the above experimental results and
[14]
previous reports,[10],
we propose the following
To gain insight into the reaction mechanism,
several control experiments were performed (Scheme
3). Initially, treatment of byproduct 2-(p-
tolylthio)naphthalene-1-ol 9 with disulfides and
iodine did not afford the desired product 3a (eq (1)),
which implied that sulfenylation/aromatization of
tetralone with disulfides is easy and the
reaction pathways as depicted in Scheme 4 for the
iodine-promoted sulfenylation/deiodination/aromatiz-
ation of 1-tetralone with disulfides. First, 1-tetralone
1 reacts with iodine to yield intermediate 14,
followed by the sulfenylation of this compound with
disulfides to afford intermediate 15. With iodine,
disulfide 2 easily transforms into 13 [15] which reacts
with 15 to give 16. Oxidation of intermediate 16
gives the byproduct 2-sulfanylnaphthol 9 in the
presence of iodine.[10] Alternatively, intermediate 16
undergoes intramolecular nucleophilic addition to
give sulfonium salt 17. Deprotonation of 17 affords
deoxygenation
process
proceeds
prior
to
aromatization. Subsequently, the commonly used free
radical inhibitor, 2,6-di-tert-butyl-4-methylphenol
(BHT), was tested to elucidate the nature of the
reaction. Addition of the 2.0 equiv. of BHT to the
3
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10.1002/adsc.201801562
Advanced Synthesis & Catalysis
dihydronaphthalene 18 or 20. Then, a [1,5]-
sigmatropic hydrogen shift of 18 leads to the
production of alkene 19.[14] Elimination of HOI from
19 gives 2-naphthyl thioethers via path a. Meanwhile,
alkene 20 could also undergo elimination to generate
1-naphthyl thioethers via path b with extrusion of
HOI.
apparent yield loss. The current study bridges the
deoxygenation and sulfenylation/aromatization of
ketones, thus providing a new tool in organic
synthesis.
Experimental Section
To a solution of disulfides 2 (0.10 mmol) in CHCl3 (1.5
mL) was added tetralones 1 (0.20 mmol) and I2 (50.76 mg,
0.20 mmol). The resulting mixture was stirred at 90 °C (oil
bath) under air for 12 h, cooled to room temperature, and
purified by silica gel chromatography, eluting with
petroleum ether to give mainly desired product 3 or 4.
Acknowledgments
This work was financially supported by the National Natural
Science Foundation of China (21502182, 21102179 and
21572271), Qing Lan Project of Jiangsu Province, National
Found for Fostering Talents of Basic Science (J1030830), the
Fundamental Research Funds for the Central Universities
(3010050077), Young Teachers’ Research Funding from the
College of Science, China Pharmaceutical University
(2018CSYT008) and Double First-Class University project
(CPU2018GY35).
Scheme 4. Possible Reaction Pathway for the Synthesis of
3 and 7.
References
Possible reaction pathways have also been
proposed for the iodine-promoted reaction of 2-
naphthyl thioether from 2-tetralone with disulfides
(Scheme 5). 2-Tetralone is activated in the presence
of iodine, thus forming intermediate 21, which
undergoes a regioselective sulfenylation reaction with
disulfide 13 to give intermediate 22. Subsequently,
intermediate 22 undergoes an intramolecular
nucleophilic addition, deprotonation, and elimination
of HOI to give 2-naphthyl thioether 6 as the exclusive
product.
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Scheme 5. Possible Reaction Pathway for the Synthesis of
6 from 2-Tetralone with Disulfides.
In summary, we have developed an iodine-
promoted sulfenylation/deoxygenation/aromatization
reaction of 1-tetralones with disulfides to give
structurally diverse naphthyl thioethers in moderate
to excellent yields. The different reaction conditions
lead to a switched regioselectivity, and therefore, 2-
naphthyl thioethers and 1-naphthyl thioethers could
be obtained. Furthermore, when the reaction was
extended to 2-tetralones, 2-naphthyl thioethers were
obtained as sole products. All of these reactions show
a wide substrate scope and functional-group tolerance.
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10.1002/adsc.201801562
Advanced Synthesis & Catalysis
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5
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Advanced Synthesis & Catalysis
UPDATE
Iodine-Promoted Tunable Synthesis of 2-Naphthyl
Thioethers and 1-Naphthyl Thioethers
Adv. Synth. Catal. Year, Volume, Page – Page
Yishu Bao,a Xiuqin Yang,a Zonghao Dai,a Suyu Ji,a
Qingfa Zhou a* and Fulai Yanga*
6
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